Base by Base

Beckner RL et al., PNAS - This episode examines a PNAS study using Chiral Inversion Mutagenesis (ChIM) to scan low-complexity domains (LCDs) of Emerin and neurofilament light chain (NEFL). Targeted L-to-D amino acid inversions reveal position-dependent, chirality-sensitive hotspots that control LCD self-association. Key terms: chiral inversion, low-complexity domains, Emerin, neurofilament light c...

Graff A et al., PNAS - A PNAS study linking global population-genetic data and structural linguistic features finds an inverse correlation: regions with lower genetic diversity show higher structural linguistic diversity, after controlling for geography, phylogeny, and environment. Key terms: linguistic diversity, population genetics, Wright's F, language contact, structural typology. Study Highli...

Avery NG et al., PNAS - This episode covers a PNAS study reporting the de novo design of miniprotein inhibitors targeting porcine deltacoronavirus (PDCoV). The lead minibinder, MB11, binds the PDCoV RBD with picomolar affinity, broadly neutralizes diverse deltacoronaviruses, and resists multiple biochemical stresses. Key terms: Porcine deltacoronavirus, miniprotein inhibitor, MB11, protein design,...

Mantecon M et al., Human Genetics and Genomics Advances - This episode reviews a brief communication reporting a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Functional studies in patient fibroblasts show decreased CHCHD4 protein, marked assembly defects of mitochondrial complexes I and IV, and broad downregulation of electron...

Lassen F et al., The American Journal of Human Genetics - Meta-analysis of up to 948,690 exome- or whole-genome-sequenced individuals across six biobanks used statistical phasing to infer compound-heterozygous genotypes, increasing detectable bi-allelic damaging genotypes by 19% and identifying 58 significant gene-trait associations, 17 of which show stronger recessive effects. Key terms: recessiv...

Sanders CG et al et al., PNAS - Surveillance-derived influenza D virus (IDV) isolates were tested across cell lines, primary airway cultures, and precision-cut lung slices to assess human compatibility. IDV replicated to high titers in human respiratory models while eliciting muted interferon responses, highlighting a potential zoonotic threat and the need for enhanced surveillance. Key terms: inf...

Costantino L et al., PNAS - Costantino et al. dissect how Eco1-mediated acetylation of Smc3 (K112, K113) and cohesin ATPase activity separately regulate chromatin loop size, loop positioning, and sister chromatid tethering in budding yeast using Micro-C XL, ChIP, and biochemical ATPase assays. Key terms: cohesin, acetylation, ATPase, chromatin loops, sister chromatid cohesion. Study Highlights: Us...

Schubert HA et al., PNAS - This episode reviews a global analysis showing that shifts in population sex composition have reversed historical sex gaps in fertility. Using UN World Population Prospects 2024 data and regression and standardization methods, the authors estimate male total fertility rates and project widening differences through 2100 driven by masculinized reproductive-age populations....

Boumasmoud M et al., PNAS - Reciprocal transplant experiments in anaerobic microcosms show that resident human gut microbiome context alters growth of introduced Escherichia coli strains and that microbially mediated acidification, driven by a Clostridium butyricum strain, can reproducibly suppress E. coli and reshape community fermentation profiles. Key terms: gut microbiome, Escherichia coli, in...

Harris M et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines a PNAS study that uses a domain-adaptive neural network to detect and classify selective sweeps in over 800 ancient and modern Eurasian genomes spanning ~7,000 years. The work recovers known targets (HLA, LCT, OCA2/HERC2, KITLG), reports 32 novel ancient sweep candidates, finds hard sweeps predominate,...

Jaggers TN et al et al., PNAS - A spontaneous OPA1 A8S missense mutation in rhesus macaques produces retinal ganglion cell loss, RNFL thinning, optic nerve atrophy, OPA1 mislocalization, and mitochondrial abnormalities, creating a nonhuman primate model that mirrors human autosomal dominant optic atrophy. Key terms: OPA1, autosomal dominant optic atrophy, rhesus macaque, retinal ganglion cell, mit...

Hou P et al., PNAS - This study combines kinetic assays and X‑ray crystallography to show how 8‑oxo‑guanosine triphosphate (8‑oxo‑rGTP) is incorporated by RNA polymerase II and how its pairing geometry with template bases (dC vs dA) differentially alters incorporation efficiency, extension, and proofreading, thereby introducing transcription‑coupled RNA damage. Key terms: RNA damage, 8-oxo-rGTP, R...

Wang Y et al et al., PNAS - This episode covers a PNAS study describing v96, a personalized plasma cell-free DNA assay that tracks up to 96 patient-specific mutations to sensitively quantify measurable residual disease (MRD) in AML patients before and after allogeneic hematopoietic cell transplantation. Key terms: cell-free DNA, measurable residual disease, acute myeloid leukemia, hematopoietic ce...

Holta KB et al., Proceedings of the National Academy of Sciences (PNAS) - This episode explains a quantitative framework for diffusion on spatially embedded dynamic mitochondrial networks. The study combines analytic theory, agent-based simulations, and live-cell imaging to show how connectivity, fusion/fission, and mobility set biomolecular mixing on mitochondrial populations. Key terms: mitochon...

Kimchi O et al., PNAS - This computational study shows that self-complementary RNA regions (palindromes) can drive sequence-specific homotypic clustering by enabling multivalent intermolecular base pairing, and that Drosophila nanos and pgc mRNAs are enriched for accessible, strong palindromes. Key terms: RNA palindromes, homotypic clustering, germ granules, nanos mRNA, phase separation. Study Hig...

Scartozzi AC et al., Human Genetics and Genomics Advances - This episode reviews a GWAS of speech rhythm (prosody) perception using the TOPsy task (n≈1,501 European-ancestry), reporting 14 suggestive loci, nominal enrichment for songbird vocal-learning gene sets, and polygenic links to reading and musical rhythm. Key terms: prosody, speech rhythm, genetics, musical rhythm, reading. Study Highlight...

Kühnisch J et al., Human Genetics and Genomics Advances 7, 100598 (2026) - Case report and tissue analysis linking a homozygous TNNI3 nonsense variant (c.406C>T; p. Arg136*) to early-onset, treatment-refractory restrictive cardiomyopathy in a young child who required heart transplantation. Key terms: TNNI3, restrictive cardiomyopathy, pediatric cardiomyopathy, troponin I, protein truncation. St...

López-Astacio RA et al., PNAS - Analysis of 60 years of feline panleukopenia virus genomes traces the origins of canine parvovirus, identifies vaccine-derived sequences, and documents distinct evolutionary rates and capsid adaptations that enabled a host jump to dogs. Key terms: parvovirus, FPV, CPV, host jump, evolution. Study Highlights: Using full-genome sequencing and phylogenetics, the author...

Tovar A et al., Human Genetics and Genomics Advances - This episode examines a study that used a modular MPRA to test ~11,656 genomic fragments from T2D- and metabolic trait-associated regions in pancreatic beta cells, comparing upstream vs downstream positions and SCP1 vs INS promoters. The work identifies promoter- and position-dependent regulatory activity and implicates HNF1 motifs in INS prom...

Widding-Havneraas T et al., PNAS - This study uses genetic variation related to educational attainment as a quasi-experimental instrument (Mendelian randomization) together with Norwegian registry data to estimate the causal return to an additional year of schooling on labor-market earnings. Key terms: returns to education, Mendelian randomization, polygenic index, Norwegian registries, life-cycle...

Imai A et al., Proceedings of the National Academy of Sciences (PNAS) - This paper shows that alternative splicing of a 12-nt microexon (meB) in Ptprd is regulated by a genetic intronic enhancer and an activity-dependent intronic silencer to set region- and age-specific ratios of PTPRD splice variants. Manipulating these intronic elements in mice changes the proportion of meB-containing isoforms w...

Korfmann K et al., Proceedings of the National Academy of Sciences (PNAS) - This episode examines cxt, a decoder-only transformer that performs next-coalescence prediction by translating local mutational context into pairwise TMRCA estimates. Trained on stdpopsim simulations, cxt delivers rapid, scalable coalescence-time inference, calibrated posteriors, and practical adaptations for empirical dat...

Tibbe D et al., The American Journal of Human Genetics - This study identifies bi-allelic hypomorphic WDHD1 variants in 17 subjects with a clinical spectrum from fetal lethality to microcephalic primordial dwarfism and characterizes cellular defects in patient-derived cells linked to replisome dysfunction. Key terms: WDHD1, microcephalic primordial dwarfism, replication stress, sister chromatid co...

Katzourou IK et al., The American Journal of Human Genetics - Population analysis of ~459,000 UK Biobank participants shows that carriers of neurodevelopmental CNVs (ND-CNVs) have higher odds of co-occurring internalizing (depression, anxiety, somatic) and cardiometabolic conditions (hypertension, dyslipidemia, obesity, T2D, CKD). Effects are stronger for deletions than duplications, greater in fe...

Sapp JC et al., The American Journal of Human Genetics - A longitudinal study of recipients of medically actionable secondary genomic findings develops a Bayesian approach that integrates variant, family genotypic, and phenotypic data to estimate the probability that a secondary finding represents a true clinicomolecular diagnosis, with a detailed analysis of BRCA1/BRCA2 families and implications...